Ethanol is known to be metabolized to acetate primarily in the liver of man and experimental animals. The acetate formed, which represents a quantitatively major foodstuff in ethanol consumers, is released from the liver and is oxidized predominantly by extrahepatic tissues - notably heart and skeletal muscle. Thus, it is proposed that the excessive production of NADH in the cytosol is primary to disturbances of metabolism of lipids, carbohydrate and protein in the liver (e.g. fatty liver, decreased gluconeogenesis and unreagenesis), whereas the dominant effect on muscle is related to the combustion of the large amounts of acetate derived from ethanol. The oxidation of acetate in muscle is linked to a rapid flux of ATP to AMP as a result of the step of acetate activation. This obligatory step which, on a quantitative basis is unique to acetate, effects changes in the steady-state phosphate potential, and is experimentally coincident with increases in the reducing 'pressure' (increased NADH/NAD ratio) and the level of citrate cycle intermediates, and decreases in the cellular concentrations of pyruvate and alanine. The influence of ethanol in perturbing fluxes of carbohydrate, lipids and amino acids in liver will be evaluated using reconstructed liver fractions containing mitochondria and cytosol enzymes which make the system competent for trans-membrane flow of reducing equivalents, fatty acid synthesis and synthesis of glucose or its precursors. Parallel studies will be performed with intact hepatocytes. In a similar manner, the effects of acetate on muscle metabolism will be evaluated using isolated muscle and heart mitochondria, 'reconstructed' cell-free systems and perfused organ preparations. BIBLIOGRAPHIC REFERENCES: E. Jack Davis and L. Lumeng, "Regulation of the Steady-State Extramitochondrial Phosphorylation Potentials by Palmityl-CoA and Atractyloside". Proc. Fed. Europ. Biochem Soc. (10th meeting, Paris, Abstract 1440 (1975). L. Lumeng, J. Bremer and E. Davis, "Suppression of the Mitochondrial Oxidation of (minus) Palmitylcarnitine by Malate-Aspartate and alpha-Glycerophosphate Shuttles". J. Biol. Chem. 251, 277-284 (1976).